Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
J Immunol. 2010 Mar 1;184(5):2539-50. doi: 10.4049/jimmunol.0901813. Epub 2010 Jan 27.
With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-kappaB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.
随着多药耐药感染发病率的迅速上升，人们对宿主防御肽作为生产新型抗菌治疗药物的模板产生了浓厚的兴趣。天然肽是先天免疫反应的多功能介质，具有一些直接的抗菌活性和多样化的免疫调节特性。我们之前开发了一种先天防御调节剂 (IDR) 1，它通过对宿主免疫的影响来介导对细菌感染的保护活性，这是一种新的抗感染治疗方法。在这项研究中，根据其在人类 PBMC 中诱导趋化因子的能力，从抗菌肽衍生物文库中选择了一种免疫调节肽 IDR-1002。该肽在体外的趋化因子诱导活性增强与体内金黄色葡萄球菌侵袭性感染模型中的保护活性增强相关，与 IDR-1 相比，保护剂量降低了 5 倍以上。IDR-1002 还能抵抗革兰氏阴性细菌病原体大肠杆菌。发现 IDR-1002 的趋化因子诱导是通过 Gi 偶联受体以及 PI3K、NF-κB 和 MAPK 信号通路介导的。该肽的保护活性与体内趋化因子产生的增强以及中性粒细胞和单核细胞向感染部位的募集有关。这些结果强调了宿主防御肽趋化因子诱导活性的重要性，并表明优化肽的体外趋化因子诱导特性是一种很有前途的方法，可以合理开发具有增强抗感染活性的免疫调节 IDR 肽。
